Impact of AUC/MIC ratios on the pharmacodynamics of the des-F(6) quinolone garenoxacin (BMS-284756) is similar to other fluoroquinolones.

Sir, Garenoxacin (BMS-284756) is a new des-F(6) quinolone that exhibits enhanced potency against Streptococcus pneumo-niae compared with clinically available fluoroquinolones. 1 Although this antibiotic lacks the C-6 fluorine, its antibac-terial mechanism of action against DNA gyrase appears to be the same as that of other quinolones. 2 It is well established that the AUC/MIC ratio is an important pharmacodynamic parameter influencing quinolone efficacy, and AUC/MIC ratios of ∼30 or higher have been shown to be sufficient to eradicate S. pneumoniae from in vitro pharmacodynamic models (IVPM). 3,4 A similar minimum target has been reported for the eradication of S. pneumoniae from community-acquired respiratory tract infections. 5 This study was designed to evaluate the impact of AUC/MIC ratios on the pharmaco-dynamics of garenoxacin. Three isolates of S. pneumoniae were selected for this study. Susceptibility tests with levofloxacin and garenoxacin against these three isolates were carried out by macrobroth dilution methodology with THB as the test medium, since it was the medium used for the pharmacodynamic studies. In addition, MICs were determined using 0.2 mg/L increments to more accurately define AUC/MIC ratios. The MICs of garenoxacin for the S. pneumoniae isolates were 0.2 mg/L for S. pneumoniae 315, 1.4 mg/L for S. pneumoniae 316 and 3.0 mg/L for S. pneumoniae 317. The MICs of levofloxacin for S. pneumoniae were 2 mg/L for S. pneumoniae 315 and 32 mg/L for S. pneumoniae 316 and 317. Nucleotide sequence analysis of the quinolone resistance-determining regions of S. pneumoniae 316 and 317 demonstrated that these resistant strains had mutations within the genes for both DNA gyrase and topoisomerase IV. Pharmacodynamic studies were carried out in THB at 37°C in ambient air using a previously described two-compartment IVPM. 3,4 Logarithmic-phase cultures (5 × 10 7 cfu/mL) were introduced into the peripheral compartment of the IVPM and were exposed to the peak concentrations of garenoxacin that were approximately two-to threefold above the MIC (0.6 or 6 mg/L). Garenoxacin was also dosed at the same concentrations at 24 h. Since garenoxacin and other fluoroquinolones kill bacteria in a concentration-dependent manner, AUC/MIC ratios were varied by altering rates of elimination rather than peak concentrations. Therefore, any differences in pharmaco-dynamic killing could be related to differences in AUC/MIC ratios and the time concentrations remained above the MIC, not peak/MIC ratios. The low range of peak/MIC ratios (2:1 to 3:1) was selected because investigators have reported that the AUC/MIC ratio is most …